Multi-omics comparisons of p-aminosalicylic acid (PAS) resistance in folC mutated and un-mutated Mycobacterium tuberculosis strains
ABSTRACTp-Aminosalicylic acid (PAS) is an important second-line antibiotic for treating multidrug-resistant tuberculosis (MDR-TB). Due to gastrointestinal disturbance and intolerance, its potent and efficacy in the treatment of extensively drug-resistant (XDR)-TB commonly are poor. Thus, it is impor...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2019-01-01
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| Series: | Emerging Microbes and Infections |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/22221751.2019.1568179 |
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| author | Wenjing Wei Huimin Yan Jiao Zhao Haicheng Li Zhenyan Li Huixin Guo Xuezhi Wang Ying Zhou Xiaoli Zhang Jincheng Zeng Tao Chen Lin Zhou |
| author_facet | Wenjing Wei Huimin Yan Jiao Zhao Haicheng Li Zhenyan Li Huixin Guo Xuezhi Wang Ying Zhou Xiaoli Zhang Jincheng Zeng Tao Chen Lin Zhou |
| author_sort | Wenjing Wei |
| collection | DOAJ |
| description | ABSTRACTp-Aminosalicylic acid (PAS) is an important second-line antibiotic for treating multidrug-resistant tuberculosis (MDR-TB). Due to gastrointestinal disturbance and intolerance, its potent and efficacy in the treatment of extensively drug-resistant (XDR)-TB commonly are poor. Thus, it is important to reveal the mechanism of susceptibility and resistance of Mycobacterium tuberculosis (Mtb) to this drug. Herein, we screened and established PAS-resistant (PASr) folC mutated and un-mutated Mtb strains, then utilized a multi-omics (genome, proteome, and metabolome) analysis to better characterize the mechanisms of PAS resistance in Mtb. Interestingly, we found that promotion of SAM-dependent methyltransferases and suppression of PAS uptake via inhibiting some drug transport associated membrane proteins were two key pathways for the folC mutated strain evolving into the PASr Mtb strain. However, the folC un-mutated strain was resistant to PAS via uptake of exogenous methionine, mitigating the role of inhibitors, and promoting DfrA, ThyA and FolC expression. Beyond these findings, we also found PAS resistance in Mtb might be associated with the increasing phenylalanine metabolism pathway. Collectively, our findings uncovered the differences of resistant mechanism between folC mutated and un-mutated Mtb strains resistant to PAS using multi-omics analysis and targeting modulators to these pathways may be effective for treatment of PASr Mtb strains. |
| first_indexed | 2024-03-08T21:58:44Z |
| format | Article |
| id | doaj.art-213e990699cb4058828432fedd709e57 |
| institution | Directory Open Access Journal |
| issn | 2222-1751 |
| language | English |
| last_indexed | 2024-03-08T21:58:44Z |
| publishDate | 2019-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Emerging Microbes and Infections |
| spelling | doaj.art-213e990699cb4058828432fedd709e572023-12-19T16:09:57ZengTaylor & Francis GroupEmerging Microbes and Infections2222-17512019-01-018124826110.1080/22221751.2019.1568179Multi-omics comparisons of p-aminosalicylic acid (PAS) resistance in folC mutated and un-mutated Mycobacterium tuberculosis strainsWenjing Wei0Huimin Yan1Jiao Zhao2Haicheng Li3Zhenyan Li4Huixin Guo5Xuezhi Wang6Ying Zhou7Xiaoli Zhang8Jincheng Zeng9Tao Chen10Lin Zhou11Center for Tuberculosis Control of Guangdong Province, Guangzhou, People’s Republic of ChinaDongguan Key Laboratory of Medical Bioactive Molecular Development and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, People’s Republic of ChinaJinan University, Guangzhou, People’s Republic of ChinaCenter for Tuberculosis Control of Guangdong Province, Guangzhou, People’s Republic of ChinaCenter for Tuberculosis Control of Guangdong Province, Guangzhou, People’s Republic of ChinaCenter for Tuberculosis Control of Guangdong Province, Guangzhou, People’s Republic of ChinaCenter for Tuberculosis Control of Guangdong Province, Guangzhou, People’s Republic of ChinaSchool of Stomatology and Medicine, Foshan University, Foshan, People’s Republic of ChinaSchool of Stomatology and Medicine, Foshan University, Foshan, People’s Republic of ChinaDongguan Key Laboratory of Medical Bioactive Molecular Development and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, People’s Republic of ChinaCenter for Tuberculosis Control of Guangdong Province, Guangzhou, People’s Republic of ChinaCenter for Tuberculosis Control of Guangdong Province, Guangzhou, People’s Republic of ChinaABSTRACTp-Aminosalicylic acid (PAS) is an important second-line antibiotic for treating multidrug-resistant tuberculosis (MDR-TB). Due to gastrointestinal disturbance and intolerance, its potent and efficacy in the treatment of extensively drug-resistant (XDR)-TB commonly are poor. Thus, it is important to reveal the mechanism of susceptibility and resistance of Mycobacterium tuberculosis (Mtb) to this drug. Herein, we screened and established PAS-resistant (PASr) folC mutated and un-mutated Mtb strains, then utilized a multi-omics (genome, proteome, and metabolome) analysis to better characterize the mechanisms of PAS resistance in Mtb. Interestingly, we found that promotion of SAM-dependent methyltransferases and suppression of PAS uptake via inhibiting some drug transport associated membrane proteins were two key pathways for the folC mutated strain evolving into the PASr Mtb strain. However, the folC un-mutated strain was resistant to PAS via uptake of exogenous methionine, mitigating the role of inhibitors, and promoting DfrA, ThyA and FolC expression. Beyond these findings, we also found PAS resistance in Mtb might be associated with the increasing phenylalanine metabolism pathway. Collectively, our findings uncovered the differences of resistant mechanism between folC mutated and un-mutated Mtb strains resistant to PAS using multi-omics analysis and targeting modulators to these pathways may be effective for treatment of PASr Mtb strains.https://www.tandfonline.com/doi/10.1080/22221751.2019.1568179P-Aminosalicylic acidmulti-omicsMycobacterium tuberculosisfolC |
| spellingShingle | Wenjing Wei Huimin Yan Jiao Zhao Haicheng Li Zhenyan Li Huixin Guo Xuezhi Wang Ying Zhou Xiaoli Zhang Jincheng Zeng Tao Chen Lin Zhou Multi-omics comparisons of p-aminosalicylic acid (PAS) resistance in folC mutated and un-mutated Mycobacterium tuberculosis strains Emerging Microbes and Infections P-Aminosalicylic acid multi-omics Mycobacterium tuberculosis folC |
| title | Multi-omics comparisons of p-aminosalicylic acid (PAS) resistance in folC mutated and un-mutated Mycobacterium tuberculosis strains |
| title_full | Multi-omics comparisons of p-aminosalicylic acid (PAS) resistance in folC mutated and un-mutated Mycobacterium tuberculosis strains |
| title_fullStr | Multi-omics comparisons of p-aminosalicylic acid (PAS) resistance in folC mutated and un-mutated Mycobacterium tuberculosis strains |
| title_full_unstemmed | Multi-omics comparisons of p-aminosalicylic acid (PAS) resistance in folC mutated and un-mutated Mycobacterium tuberculosis strains |
| title_short | Multi-omics comparisons of p-aminosalicylic acid (PAS) resistance in folC mutated and un-mutated Mycobacterium tuberculosis strains |
| title_sort | multi omics comparisons of p aminosalicylic acid pas resistance in folc mutated and un mutated mycobacterium tuberculosis strains |
| topic | P-Aminosalicylic acid multi-omics Mycobacterium tuberculosis folC |
| url | https://www.tandfonline.com/doi/10.1080/22221751.2019.1568179 |
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